Akt is a multi-functional oncogenic kinase that plays critical roles in normal and diseased cells. Hyper-activation of Akt is one of the most common molecular alterations in cancer. There are three similar forms of Akt and evidence suggests that these forms can play different roles in human cancer. It is not known if a specific Akt isoform is responsible for promoting High Grade Glioma (HGG) tumors. My preliminary data suggest that 2 of the 3 forms are important for malignant progression. A major objective of this proposal is to identify the Akt form and their downstream substrates that causes malignant progression in HGG. A second objective is to find patient subgroups that use different Akt forms and downstream Akt substrates. We will do this by finding the Akt form and downstream substrates that is associated with worse tumor behavior and use clustering techniques to find subgroups. We will also identify how Akt forms promote malignancy. If we identify the Akt form and their downstream substrates that drive malignancy then we can develop inhibitors that shut down important points in the pathway. We think that shutting down the right proteins will be an effective treatment for HGG tumors with little toxicity. We also are investigating ways to classify tumor subgroups for therapy selection using Akt pathway subgroups. This re-entry training grant has been designed to acquire necesary experience in biostatistics, bioinformatics and the use of reverse phase protein arrays. The training described in this proposal will provide the capability to establish professional networks, study areas that have progressed rapidly in my absence and acquire the skills to become a successful independent scientist. PUBLIC HEALTH RELEVANCE: Akt is a protein that is often responsible for driving cancer cell growth, spread and resistance to conventional and experimental therapies. Drugs that inhibit the malignancy-associated parts of the Akt pathway may be very effective against glioma tumors with decreased toxicity. Here we propose to identify 'arms' of the Akt pathway that are specific to cancer cells and are ideal targets for developing effective molecular therapies. We will also find ways to identify tumor subgroups that use different arms of the Akt pathway and understand which proteins and pathways are active in tumor subgroups.